Recro Pharma Inc.Meloxicam Injection, 30 mg/mL

NDA 210583 COMPLETE RESPONSE

Recro Pharma Inc. 490 Lapp Road Malvern, PA 19355

Attention: Diane P. Myers, SVP, Regulatory and Quality

Dear Ms. Myers:

Please refer to your New Drug Application (NDA) dated and received July 26, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA), for Meloxicam Injection, 30 mg/mL.

We acknowledge receipt of your amendment dated September 24, 2018, which constituted a complete response to our May 23, 2018, action letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

CLINICAL

1. Meloxicam Injection has an onset of action in the range of 2 to 3 hours (possibly longer if patients receiving early rescue had been excluded from this analysis). The delayed onset fails to adequately meet prescriber expectations for intravenous (IV) drugs. Meloxicam Injection is unfit for use as an IV drug for acute pain as monotherapy. Furthermore, the analgesic effect wanes approximately 18 hours after dosing. This makes Meloxicam Injection of questionable utility as a component of multimodal analgesic therapy when dosed every 24 hours, as one would expect the dosing instructions to reflect adequate | efficacy throughout the dosing interval. The proposal to label the product

based on pharmacokinetic modeling, fails to adequately address the efficacy deficiencies noted and does not provide a benefit that could outweigh the additional safety risks ciated with the higher meloxicam levels that would result from a shorter dosing interval.

(b) (4)

a. Regarding efficacy, the available efficacy and pharmacokinetic data do not support a finding of an exposure/response relationship suitable to rely on pharmacokinetic modeling to support a change in dosing interval. Measures of pain intensity are not

Reference ID: 4683948

NDA 210583

Page 2

well correlated with drug concentration data at the same time point. Specifically, high plasma meloxicam concentrations are achieved shortly after the first dose but the median onset of pain relief is not reported until Hour 2 or 3. The pharmacokinetic data also do not explain the end-of-dose failure as there is little change in plasma meloxicam levels between Hours 18 and 24, (a decline from approximately 1700 ng/mL to approximately 1500 ng/mL). Therefore, the proposed changes to dosing instructions do not adequately address the observed efficacy deficiencies.

b. The available safety data for Meloxicam Injection are inadequate to support the safety (b) (4)

Many of the adverse events associated with nonsteroidal anti- inflammatory drugs such as meloxicam are dose- and exposure-related. The meloxicam levels predicted by the pharmacokinetic modeling are higher than the

measured levels with 24-hour dosing. si

PRESCRIBING INFORMATION

2.

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the prescribing information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

CARTON AND CONTAINER LABELING

3.

Reference ID: 4683948

We refer to your revised draft carton and container labeling submitted on February 25, 2019. When you resubmit your application, revise the draft carton and container labeling as follows:

1. Container Label a. Add the lot number in accordance with 21 CFR 201.10(i)(1).

b. Add the expiration date in accordance with 21 CFR 201.17 and 21 CFR 211.137. Additionally, to minimize confusion and reduce the risk for deteriorated drug medication errors, identify the format you intend to use. FDA recommends that the human-readable expiration date on the drug package label include a year, month, and non-zero day. FDA recommends

NDA 210583 Page 3

that the expiration date appear in YY YY-MMDD format if only numerical characters are used or in YY YY-MMM-DD if alphabetical characters are used to represent the month. If there are space limitations on the drug package, the human-readable text may include only a year and month, to be expressed as: YYYY-MM if only numerical characters are used or YY YY-MMM if alphabetical characters are used to represent the month. FDA recommends that a hyphen or a space be used to separate the portions of the expiration date.

2. Carton Labeling-Single Vial

3. Carton Labeling

a. In September 2018, FDA released draft guidance on product identifiers

required under the Drug Supply Chain Security Act.1 The Act requires manufacturers and repackagers, respectively, to affix or imprint a product identifier to each package and homogenous case of a product intended to be introduced in a transaction in(to) commerce beginning November 27, 2017, and November 27, 2018, respectively. We recommend that you review the draft guidance to determine if the product identifier requirements apply to your product’s labeling. The draft guidance is available from: https://www.fda.gov/ucm/groups/fdagov-public/@ fdagov-drugsgen/ documents/document/ucm62 1044. pdf

b. See Container Label comments a and b.

(b) (4)

See Carton Labeling-Single Vial comment a.

PROPRIETARY NAME

4. Please refer to correspondence dated December 19, 2018, which addresses the proposed proprietary name, ANJESO. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or

dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

Reference ID: 4683948

Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

NDA 210583 Page 4

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

8. Provide English translations of current approved foreign labeling not previously submitted.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” December 2017 at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM59054 1.

Reference ID: 4683948

NDA 210583 Page 5

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Diana L. Walker, PhD, Regulatory Project Manager, at (301) 796- 4029.

Sincerely, {See appended electronic signature page}

Sharon Hertz, MD

Director

Division of Anesthesia, Analgesia, and Addiction Products

Office of Drug Evaluation IT

Center for Drug Evaluation and Research

Reference ID: 4683948

Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

SHARON H HERTZ 03/22/2019 10:30:55 AM

Reference ID: 4663948